Premium
Characterization of the α 1 ‐adrenoceptor subtype mediating contractions of the pig internal anal sphincter
Author(s) -
Mills K A,
Hausman N,
ChessWilliams R
Publication year - 2008
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/bjp.2008.217
Subject(s) - phenylephrine , prazosin , internal anal sphincter , agonist , endocrinology , medicine , potency , contraction (grammar) , intrinsic activity , chemistry , antagonist , stimulation , receptor , anal canal , biochemistry , in vitro , blood pressure , rectum
Background and purpose: The internal anal sphincter has been shown to contract in response to α 1 ‐adrenoceptor stimulation and therefore α 1 ‐adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α 1 ‐adrenoceptor subtype responsible for mediating contraction of the internal anal sphincter of the pig. Experimental approach: The potency of agonists and the affinities of several receptor subtype selective antagonists were determined on smooth muscle strips for the pig internal anal sphincter. Cumulative concentration–response curves were performed using phenylephrine and noradrenaline. Key results: The potency of the α 1A ‐adrenoceptor selective agonist A61603 (pEC 50 =7.79±0.04) was 158‐fold greater than that for noradrenaline (pEC 50 =5.59±0.02). Phenylephrine (pEC 50 =5.99±0.05) was 2.5‐fold more potent than noradrenaline. The α 1D ‐adrenoceptor selective antagonist BMY7378 caused rightward shifts of the concentration–response curves to phenylephrine and noradrenaline, yielding low affinity estimates of 6.59±0.15 and 6.33±0.13, respectively. Relatively high affinity estimates were obtained for the α 1A ‐adrenoceptor selective antagonists, RS100329 (9.01±0.14 and 9.06±0.22 with phenylephrine and noradrenaline, respectively) and 5‐methylurapidil (8.51±0.10 and 8.31±0.10, respectively). Prazosin antagonized responses of the sphincter to phenylephrine and noradrenaline, yielding mean affinity estimates of 8.58±0.10 and 8.15±0.08, respectively. The Schild slope for prazosin with phenylephrine was equal to unity (1.01±0.24), however the Schild slope using noradrenaline was significantly less than unity (0.50±0.11, P <0.05). Conclusion and implications: The results suggest that contraction of circular smooth muscle from the pig internal anal sphincter is mediated via a population of adrenoceptors with the pharmacological characteristics of the α 1A/L ‐adrenoceptor, most probably the α 1L ‐adrenoceptor form of this receptor. British Journal of Pharmacology (2008) 155 , 110–117; doi: 10.1038/bjp.2008.217 ; published online 2 June 2008